Synthesis of Sansalvamide A derivatives and their cytotoxicity in the MSS colon cancer cell line HT-29

Bioorg Med Chem. 2006 Aug 15;14(16):5625-31. doi: 10.1016/j.bmc.2006.04.031. Epub 2006 May 11.

Abstract

We report the synthesis of thirty-six Sansalvamide A derivatives, and their biological activity against colon cancer HT-29 cell line, a microsatellite stable (MSS) colon cancer cell-line. The thirty-six compounds can be divided into three subsets, where the first subset of compounds contains L-amino acids, the second subset contains D-amino acids, and the third subset contains both D- and L-amino acids. Five compounds exhibited excellent inhibitory activity (>75% inhibition). The structure-activity relationship (SAR) of the compounds established that a single D-amino acid in position 2 or 3 gave up to a 10-fold improved cytotoxicity over Sansalvamide A peptide. This work highlights the importance of residues 2 and 3 and the role of D-amino acids in the extraordinary SAR for this compound class.

Publication types

  • Research Support, N.I.H., Extramural
  • Research Support, Non-U.S. Gov't

MeSH terms

  • Amino Acids / chemistry
  • Antineoplastic Agents / chemical synthesis
  • Antineoplastic Agents / pharmacology*
  • Colonic Neoplasms / pathology
  • Depsipeptides / chemical synthesis
  • Depsipeptides / pharmacology*
  • HT29 Cells / drug effects*
  • HT29 Cells / metabolism
  • Humans
  • Inhibitory Concentration 50
  • Structure-Activity Relationship
  • Thymidine / metabolism
  • Tumor Cells, Cultured

Substances

  • Amino Acids
  • Antineoplastic Agents
  • Depsipeptides
  • sansalvamide A
  • Thymidine